Transgenic mice with randomly inserted transgenes that contain a human IL-15 sequence are known in the art. However, transgenic mice that express human IL-15 from randomly integrated transgenes are not optimal in one respect or another. For example, most mice transgenic for human IL-15 exhibit abnormal levels and/or ratios of certain cells, including lymphocytes (e.g., T cells), that are likely due to a dysregulation of immune cell function. Such mice also exhibit a panoply of pathologies, presumably ultimately due to dysregulation of the transgenic IL-15. Such dysregulation may result from, e.g., absence of endogenous control elements, and/or placement of the human IL-15 sequence away from the endogenous IL-15 locus.
There remains a need in the art for non-human animals that comprise human IL-15-encoding sequences, wherein the human IL-15 encoding sequences are at an endogenous non-human IL-15 locus, and/or are under regulatory control of endogenous non-human IL-15 elements (e.g., upstream and/or downstream noncoding regions). There is a need in the art for non-human animals that express human IL-15 under the control of endogenous non-human regulatory elements. There is a need in the art for non-human animals that express human IL-15 in a manner that is physiologically relevant in the non-human animal. There is a need in the art for non-human animals that express a human IL-15, wherein the non-human animals lack a significant abnormality in lymphocyte populations, e.g., in T cell populations. There is also a need in the art for non-human animals that express human or humanized IL-15, and that lack one or more of the pathologies exhibited by non-human animals that are transgenic for human IL-15.